The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year, there have been three major efforts underway that are targeted on this objective: 1) analysis of expressed T-cell repertoires in multiple sclerosis (MS) patients and the contribution of T-cell receptor (TCR) germline genes to susceptibility to MS; 2) dissection of the molecular basis of viral peptide-binding and presentation for T-cell recognition by HLA class I molecules; and 3) analysis of antigen presentation pathways for class I-restricted antiviral cytotoxic T- lymphocyte (CTL) responses. The principle findings are as follows: 1) analysis of T-cell responses to MBP and a foreign antigen (tetanus toxoid) by genetically identical twins who are concordant or discordant for MS indicates that there is a skewing of the TCR repertoire that correlates with the presence of MS; 2) an extension of previous studies has further localized a susceptibility gene(s) for MS to a 175-kb region of the TCR Vbeta chain locus, and has demonstrated gene complementation between this susceptibility gene(s) and an HLA class II gene; and 3) isolation and sequencing of endogenous peptides bound to the HLA class I molecule HLA-A3 has permitted identification of a specific combination of peptide anchor residues which can be used to successfully predict immunogenic T-cell epitopes within viral protein sequences.